Von Hippel-Lindau (VHL) disease in an inherited, autosomal dominant tumor predisposition syndrome caused by germline mutations in the VHL tumor suppressor gene [1, 2]. This germline mutation is found in approximately 1 in 36,000 individuals . Affected individuals are susceptible to developing hemangioblastomas (HBs) of the central nervous system (CNS) and retina, renal cell carcinomas (RCCs), endolymphatic sac tumors, pheochromocytomas and pancreatic neuroendocrine tumors [2, 4]. Patients with VHL disease can be divided into types 1 and 2, based on the probability of developing pheochromocytoma, with type 2 disease carrying the higher risk of pheochromocytoma [2, 5].
Due to the development of a variety of different benign and malignant neoplasms, patients have a median survival ranging between 40 and 52 years, the shortest amongst cancer predisposition syndromes . The leading causes of morbidity and mortality in these patients are RCC and CNS HB [7, 8]. The treatment for VHL associated RCC and CNS HB is surgery . However, if surgery is not a viable option, there are no approved systemic therapies that have gained widespread use for the treatment of VHL related CNS HB [2, 7]. The natural history of VHL-associated CNS HB was described in a recent long-term study of 225 patients with VHL. On that study, 51% of all CNS HB were stable in size during long-term follow-up and 49% of all CNS HB grew. The most common pattern of growth was saltatory (72% of growing tumors), followed by exponential (22%) and linear (6%). This led to the understanding that growth rate is necessary to assess the efficacy of surgical vs. nonsurgical therapies .
In addition, retinal HBs are typically the most common and earliest presentation of VHL disease [9, 10]. They occur in about 50% of VHL patients and are the first tumor to arise in 1 out of 3 cases. Peripheral retinal HBs can be treated with photocoagulation for small tumors and cryotherapy for larger tumors . However, these treatments cannot be used if the tumor is near the optic nerve. In such cases, the common therapeutic approach is surveillance, due to the high risk of damaging the optic nerve . Currently, surgical resection of growing, symptomatic HBs is the only treatment option for these tumors. Despite the improvement in the understanding of the pathophysiology of hemangioblastomas, no effective treatment strategy has demonstrated clinical efficacy in retinal HBs in addition to VHL associated CNS HB.
Propranolol hydrochloride an FDA approved agent, is a synthetic B1 and B2 adrenergic antagonist that has been marketed for over 50 years, and whose safety has been well reported . It is used for the treatment of hypertension, cardiac arrhythmias, and is effective in treating infantile hemangiomas (IH) [13, 14]. Moreover, IH VHL associated HBs have similar histologic appearance and pathogenesis. Albinana et. al, showed that propranolol may have efficacy in the treatment of retinal HBs, in a study where 7 patients with retinal HBs showed stable disease over a period of 12 months . In addition, a study by Shepard et. al, showed propranolol activity in in-vitro models of VHL RCC and CNS HB, in addition to retrospective data suggesting that propranolol may slow HB growth in VHL patients .
68Ga-DOTATATE positron emission tomography (PET) imaging of VHL patients has shown that VHL-HBs have avidity to somatostatin analogues [17–19]. Neuroendocrine tumors that express somatostatin receptors (SSTRs) demonstrate a clinical response to somatostatin analogue therapy [20, 21] and this has been demonstrated in VHL related pancreatic neuroendocrine tumors as well . Sizdahkhani et. al, showed that the somatostatin receptor agonist octreotide showed efficacy both in-vitro and in off label use in a patient with advanced VHL HB , suggesting that it may have potential as a therapy for VHL associated HB. Here we present a case of a patient with VHL-associated CNS HBs and retinal HBs, treated with propranolol and subsequently with Lanreotide. On both treatments, the patient showed notable symptom improvement with pain reduction and optimal sleep quality. In addition, since starting Lanreotide, the patient’s hemangioblastoma remained stable on imaging.